Stress is a contributing factor to high blood pressure, which can eventually cause
heart failure. Heart failure is a leading cause of illness, death and escalating health
care costs across the nation and in the institute's home state of South Carolina.
Connections Between Chronic Stress and Heart Failure
One type of heart failure that is increasing disproportionately is heart failure where
the heart pumps normally but is too stiff to fill properly, called heart failure with
preserved ejection fraction.
This project seeks to provide insight into pathways that contribute to this common
form of heart failure, the onset of which we believe to be exacerbated and accelerated
by stress, and provide the research foundation for a new way of treating and preventing
heart failure with preserved ejection fraction.
This research will uncover new understandings of how this particular form of heart
failure is affected by stress.
Through our interdisciplinary approach combining academic research with the ways it
can apply in a clinical setting, we seek to find new treatments for this form of heart
failure to reduce its mortality and morbidity rates.
This study will be the first to strategically target how heart failure with preserved
ejection fracture starts on the molecular level. The interdisciplinary nature of this
project allows the work to then go beyond where many purely academic research undertakings
stop, by extending findings to real-world clinical applications to identify possible
treatments and medication for this form of heart failure.
We aim to establish that the inflection point from LVPO (left ventricular pressure
overload) to HFpEF (heart failure with preserved ejection fraction) is NLRP3 (nucleotide-binding
domain, leucine-rich–containing family, pyrin domain–containing-3) inflammasone induction
which can be controlled by transgenic conditional constructs.
We aim to determine that superimposing CUS (chronic unpredictable stress) with LVPO
will accelerate the progression to HFpEF and interruption of NLRP3 will prevent this
coactivation. process. Translational relevance will be established by utilizing an
NLRP3 inhibitor with LVPO and CUS.
Hypothesis: The fundamental molecular switch in LVPO is NLRP3 induction causing a cascade of profibrotic
events leading to HFpEF progression whereby chronic, unpredictable stress will cause
a feedforward synergistic acceleration of this process.
Goal: To move the field forward by establishing that while systemic inflammation may not
be an operative pathway for HFpEF, localized metabolic stress and NLRP3 induction
is a key molecular event in the development and progression of this heart failure
Vision: We will be the first to develop tissue/cell specific silencing of NLRP3 and identify that
NLRP3 is essential for the development of HFpEF, and then pivot the small molecule
NLRP3 inhibitor (OLT1171) for use in HFpEF.
While this research improves the lives of anyone who has cardiovascular disease or
knows someone with cardiovascular disease in South Carolina—a high percentage of the
population—certain groups will benefit greatly from this focus area and the institute's
work at large.
Women and the Female Population
This research will improve the lives of anyone who has cardiovascular disease or knows
someone with cardiovascular disease in South Carolina. However, certain groups will
greatly benefit from our focus area and the institute's work at large.
Black and African American Communities
High blood pressure disproportionately affects African American communities. This
community experiences high heart failure rates despite health providers meeting standard
of care guidelines. The institute will shed light on how body responses to everyday
situations increase the likelihood of cardiovascular disease in these populations.
Veterans and Those Suffering from PTSD or Trauma
Exposure to trauma affects the body in significant ways, especially the heart and
vascular system. Veterans are at higher risk of having a new onset of heart disease
compared with non-veterans. This research contributes directly to improving the lives
of veterans and those with trauma or PTSD, while adding to the overall knowledge base
of care for veterans.